| Popis: |
The melanocortin system has been implicated in various physiological functions including pigmentation [1,2], sexual function [3], cardiovascular function [4], memory [5], and energy homeostasis [6-10]. The energy homeostasis functions have been attributed to the melanocortin 3 (MC3R) and melanocortin 4 receptors (MC4R) [6-10]. The intracerebroventricular (ICV) administration of melanocortin agonists has been reported to significantly decrease food intake, whereas administration of antagonists is reported to significantly increase food intake [9,10]. Therefore, melanocortin agonist ligands could serve as a potential treatment for obesity, and melanocortin antagonist ligands could serve as a treatment for cachexia. However, some limitations of the melanocortin ligands do exist such as modulating sexual function [3] and blood pressure [4]. It is, therefore, of interest to develop melanocortin ligands with unique pharmacologies which are void of these undesired effects. SKY 2-23-7 is a tetrapeptide which was identified in our laboratory with the sequence Ac-Trp-(p-I)DPhe-Arg-Trp-NH2 (Figure 1) [11]. It was discovered through a double substitution strategy of the melanocortin core His-Phe-Arg-Trp sequence. SKY 2-23-7 was characterized as a weak antagonist (pA2=5.43±0.16) at the mMC3R and a strong antagonist (pA2=7.83±0.16) at the mMC4R (Figure 2). Distinctly there was minimal mMC3R agonist activity up to 100 μM which is not commonly observed for a mMC3R/mMC4R antagonist such as SHU9119 [11]. The current study investigated the in vivo effects of this unique pharmacology via intracerebroventricular (ICV) administration of SKY 2-23-7 in male and female mice which gave evidence of sex specific differences. |
